The renin-angiotensin system is a complex biochemical pathway that maintains total body homeostasis of blood pressure, blood volume, and electrolyte composition. The major effector for this pathway, angiotensin II, targets multiple tissues throughout the body. Studies have demonstrated that virtually all of the physiologic actions of angiotensin II are mediated via the AT1 receptor subtype. The remarkable diversity of tissue-specific effects in response to angiotensin II-AT1 receptor binding suggests that AT1 receptor binding is only the first step in a cascade of intracellular events that transduce angiotensin II's signal from the cell surface, through the cytoplasm, and finally to the nucleus. It is these signals that convey specificity to tissue responses. In vascular smooth muscle cells, recent studies have shown that angiotensin II can act not only as a vasoactive agent, but perhaps more importantly also as a growth factor. The clinical relevance of these angiotensin II growth responses are apparent in such common disease processes as hypertension, cardiovascular hypertrophy, congestive heart failure, and vascular injury (e.g., angioplasty, atherosclerosis). However, the biochemical events that mediate angiotensin II-induced cellular growth are incompletely understood. Recently, work from this investigator as well as others have shown that protein tyrosine phosphorylation plays an essential role in the signaling responses mediated by angiotensin II. This proposal continues this laboratory's established interest in the intracellular events that transduce AT1 receptor signaling from the cell surface to the cell nucleus in cultured rat aortic smooth muscle cells. In Specific Aim 1, he proposes to study angiotensin II-induced stimulation of the JAK (janus kinase)-STAT (signal transducers and activators of transcription) cascade. In Specific Aims 2 and 3, he will focus on the role of the Src family of intracellular tyrosine kinases (e.g., pp60c-src) and tyrosine phosphatases (e.g., PTP-1D) in the angiotensin II-induced JAK-STAT pathway. The final goal of this study is to determine the role of the JAK-STAT pathway in angiotensin II-mediated vascular smooth muscle cell growth. Given the multiple tissue targets for angiotensin II, such studies will likely contribute to our understanding of both physiologic and pathologic cellular growth processes.